Renal anatomical classification systems cannot predict the occurrence of vascular complications after partial nephrectomy.

OBJECTIVES: To determine the relationship between renal tumor complexity and vascular complications after partial nephrectomy using PADUA, RENAL, and ZS scores. METHODS: Between January 2007 and December 2018, a total of 1917 patients with available cross-sectional imaging were enrolled in the study. Logistic regressions were used to identify independent predictors of vascular complications. RESULTS: Of 1917 patients, 31 (1.6%) developed vascular complications, including 10 females and 21 males. The high-complexity category was significantly associated with a decreased risk of vascular complication in PADUA (OR = 0.256; 95%CI = 0.086-0.762; P = 0.014) and ZS score (OR = 0.279; 95%CI = 0.083-0.946; P = 0.040). Laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were independent risk factors for vascular complications. Meanwhile, the incidence was significantly reduced in the recent 4 years in the high score tumor group alone in PADUA (0.2% [1/474] vs. 2.2% [3/139], P = 0.038) and ZS score (0.2% [1/469] vs. 2.7% [3/112], P = 0.024). In the first 8 years, laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were the only two independent risk factors for vascular complications. In the recent 4 years, only the high-complexity category was significantly associated with a decreased risk of vascular complication in the PADUA score (OR = 0.110; 95%CI = 0.013-0.938; P = 0.044). CONCLUSION: The renal anatomic classification system cannot predict the occurrence of vascular complications after partial nephrectomy.

Development and validation of a clinical-radiomics model for prediction of prostate cancer: a multicenter study.

PURPOSE: To develop an early diagnosis model of prostate cancer based on clinical-radiomics to improve the accuracy of imaging diagnosis of prostate cancer. METHODS: The multicenter study enrolled a total of 449 patients with prostate cancer from December 2017 to January 2022. We retrospectively collected information from 342 patients who underwent prostate biopsy at Minhang Hospital. We extracted T2WI images through 3D-Slice, and used mask tools to mark the prostate area manually. The radiomics features were extracted by Python using the "Pyradiomics" module. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for data dimensionality reduction and feature selection, and the radiomics score was calculated according to the correlation coefficients. Multivariate logistic regression analysis was used to develop predictive models. We incorporated the radiomics score, PI-RADS, and clinical features, and this was presented as a nomogram. The model was validated using a cohort of 107 patients from the Xuhui Hospital. RESULTS: In total, 110 effective radiomics features were extracted. Finally, 9 features were significantly associated with the diagnosis of prostate cancer, from which we calculated the radiomics score. The predictors contained in the individualized prediction nomogram included age, fPSA/tPSA, PI-RADS, and radiomics score. The clinical-radiomics model showed good discrimination in the validation cohort (C-index = 0.88). CONCLUSION: This study presents a clinical-radiomics model that incorporates age, fPSA/PSA, PI-RADS, and radiomics score, which can be conveniently used to facilitate individualized prediction of prostate cancer before prostate biopsy.

Reprogramming of arachidonic acid metabolism using α-terpineol to alleviate asthma: insights from metabolomics.

Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airway inflammation and mucus hypersecretion. α-Terpineol is a monocyclic terpene found in many natural plants and foods. It has been reported to possess a wide range of pharmacological activities including anti-inflammatory and expectorant effects. However, the role of α-terpineol in asthma and its potential protective mechanism have not been well elucidated. This study is designed to investigate the pharmacological effect and mechanism of α-terpineol on asthmatic mice using the metabolomics platform. A murine model of asthma was established using ovalbumin (OVA) sensitization and then challenged for one week. The leukocyte count and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory  infiltrate and mucus secretion were evaluated. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics study was performed on lung tissues and serum to explore endogenous small molecule metabolites affected by α-terpineol in asthmatic mice. After α-terpineol treatment, leukocyte count, inflammatory cytokines in the BALF, and peribronchial inflammation infiltration were significantly downregulated. Goblet cell hyperplasia and mucus secretion were attenuated, with the level of Muc5ac in BALF decreased. These results proved the protective effect of α-terpineol against airway inflammation, mucus hypersecretion and Th1/Th2 immune imbalance. To further investigate the underlying mechanisms of α-terpineol in asthma treatment, UPLC-MS/MS-based metabolomics analysis was performed. 26 and 15 identified significant differential metabolites were found in the lung tissues and serum of the control, model and α-terpineol groups, respectively. Based on the above differential metabolites, enrichment analysis showed that arachidonic acid (AA) metabolism was reprogrammed in both mouse lung tissues and serum. 5-Lipoxygenase (5-LOX) and cysteinyl leukotrienes (CysLTs) are the key enzyme and the end product of AA metabolism, respectively. In-depth studies have shown that pretreatment with α-terpineol can alleviate asthma by decreasing the AA level, downregulating the expression of 5-LOX and reducing the accumulation of CysLTs in mouse lung tissues. In summary, this study demonstrates that α-terpineol is a potential agent that can prevent asthma via regulating disordered AA metabolism.

Circ_0020123, a New Circular RNA Biomarker for Deep Vein Thrombosis in Pregnant Women.

BACKGROUND: Deep vein thrombosis (DVT) commonly occurs among vascular diseases globally, for which circular RNAs (circRNAs) are becoming a promising option by mediating functions of human umbilical vein endothelial cells (HUVECs). Therefore, this study focuses on whether circ_0020123 plays a role in HUVECs. METHODS: Pregnant women with DVT (n = 39) and without DVT (n = 39) were selected as the observation group and control group, respectively. Circ_0020123 expression in serum of pregnant women with DVT was assessed by RT-qPCR. The risk factors of DVT in pregnant women were analyzed by single factor logistic regression. HUVECs were treated with oxidized low-density lipoprotein (ox-LDL) to construct an in vitro model. Cell proliferation, tube formation ability, migration, and apoptosis were determined by cell counting kit-8, tube formation assay, Transwell assay, and flow cytometry. The levels of oxidative stress, inflammatory factors, endothelin-1 (ET-1), and von Willebrand factor (VWF) in cell supernatant were detected. RESULTS: The mode of delivery (cesarean delivery), postpartum hemorrhage (yes), puerperal bedtime (> 72 hours), and increased circ_0020123 were independent risk factors for DVT in pregnant women. Knockdown of circ_0020123 promoted HUVEC proliferation and angiogenesis in vitro. CONCLUSIONS: Clinical analysis of risk factors for DVT in pregnant women and positive measures for prevention can effectively avoid the formation of DVT. Circ_0020123 is a new circRNA biomarker for DVT in pregnant women.

Dynamic nanoassemblies derived from small-molecule homodimeric prodrugs for in situ drug activation and safe osteosarcoma treatment.

Supramolecular prodrug self-assembly is a cost-effective and powerful approach for creating injectable anticancer nanoassemblies. Herein, we describe the self-assembly of small-molecule prodrug nanotherapeutics for tumor-restricted pharmacology that can be self-activated and independent of the exogenous stimuli. Covalent dimerization of the anticancer agent cabazitaxel via reactive oxygen species (ROS)- and esterase-activatable linkages produced the homodimeric prodrug diCTX, which was further coassembled with an ROS generator, dimeric dihydroartemisinin (diDHA). The coassembled nanoparticles were further refined in an amphiphilic matrix, making them suitable for in vivo administration. The ROS obtained from the coassembled diDHA synergized with intracellular esterase to activate the neighboring diCTX, which in turn induced potent cytotoxicity. In a preclinical orthotopic model of human osteosarcomas, nanoparticle administration exhibited durable antitumor efficacy. Furthermore, this smart, dual-responsive nanotherapeutic exhibited lower toxicity in animals than those of free drug combinations. We predict that this platform has great potential for further clinical translation.

Evaluation of the safety and efficacy of perform enterectomy in colorectal cancer patients aged 80 or older. A meta-analysis and a systematic review.

BACKGROUND: Colorectal cancer (CRC) is one of the four most common cancers in the world. At present, human beings have stepped into an aging society, and the number of over eighties colorectal cancer patients has increased year by year. However, few high-quality studies focused on the post-operation complications and long-term outcomes of octogenarian patients with colorectal cancer. This meta-analysis, based on published studies, aims to assess the safety of treating octogenarian CRC patients with surgery. METHODS: Databases, including PubMed, Embase, and Cochrane Library were searched until July 2022. The incidence of preoperative comorbidities, postoperative complications, and mortality was assessed using odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Furthermore, the hazard ratios (HRs) with 95% CIs were applied for survival outcomes. RESULTS: A total of 13,790 patients with CRC in 21 studies were included. Our results demonstrated that octogenarian patients were associated with a higher burden of comorbidities (OR = 3.03; 95% CI: 2.03, 4.53; P = .000), high incidences of overall postoperative complications (OR = 1.63; 95% CI: 1.29, 2.06; P = .000), high internal medicine postoperative complications (OR = 2.38; 95% CI: 1.76, 3.21; P = .000), high in-hospital mortality (OR = 4.01; 95% CI: 3.06, 5.27; P = .000) and poor overall survival (OR = 2.13; 95% CI: 1.78, 2.55; P = .000). But there is no statistical difference in surgery-related postoperative complications(OR = 1.16; 95% CI: 0.94, 1.43; P = .16) and DFS (OR = 1.03; 95% CI: 0.83, 1.29; P = .775). CONCLUSIONS: Extremely elderly patients with colorectal cancer have the high burden of comorbidities, high postoperative complications and mortality. However, survival outcomes (DFS) in patients 80 years and older are similar to younger patients. Clinicians should administer individualized treatment for such patients. Physiologic age rather than chronological age should determine cancer management for each individual.

Comparison of current treatment strategy for osteonecrosis of the femoral head from the perspective of cell therapy.

Aims: The purpose of our study is to compare the effects of core decompression (CD) and bone grafting (BG) on osteonecrosis of the femoral head (ONFH). And evaluate the efficacy of CD based on cell therapy to provide guidance for the dose and number of cells. Methods: We searched PubMed, Embase, and the Cochrane Library between 2012 and 2022, with keywords including "osteonecrosis of the femoral head", "core decompression" and "bone grafting". We selected comparative studies of CD and BG, and the comparison of CD combined with bone marrow (BM) transplantation and CD alone. Changes in hip pain were assessed by VAS, hip function were assessed by HHS and WOMAC, and THA conversion rate was used as an evaluation tool for femoral head collapse. From these three aspects, the dose of bone marrow and the number of cells transplantation were subgroup analyzed. Results: Eleven studies were used to compare the efficacy of CD and BG. There was no significant difference in HHS, and the THA conversion rate of BG was significantly lower than that of CD. Thirteen CD studies based on cell therapy were included in the meta-analysis. Bone marrow aspiration concentrate (BMAC) can significantly improve VAS (mean difference (MD), 10.15; 95% confidence intervals (CI) 7.35 to 12.96, p < 0.00001) and reduce THA conversion rate (odds ratio (OR), 2.38; 95% CI 1.26 to 4.47, p = 0.007). Medium dose bone marrow fluid has a lower p-value in THA conversion rate. The p values of bone marrow mononuclear cells (BMMC) of 109 magnitude in VAS score were lower. Conclusion: In general, there is no consensus on the use of BG in the treatment of ONFH. The enhancement of cell-based CD procedure shows promising results. Using 20 mL BMAC and 109 magnitude BMMC is likely to achieve better results.

Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination.

Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.

Prognostic evaluation based on radiological morphological characteristic for tumors larger than 7 cm in renal cell carcinoma.

PURPOSE: To predict survival prognosis of renal cell carcinoma (RCC) patients with tumors larger than 7 cm by preoperative radiological morphological features. METHODS: We reviewed the medical records of RCC patients with tumors larger than 7 cm from 2007 to 2017 in Zhongshan Hospital, Fudan University. A total of 251 patients' clinical data were collected. 25 and 9 patients were excluded due to loss of follow-up and lack of imaging data, respectively. PFS and OS from date of surgery were evaluated. We defined the irregularity of the tumor as the morphological feature studied and quantified it according to a theorem of the ellipse: the length from the midpoint of the ellipse to any point on the ellipse is shorter than or equal to 1/2 of the long axis. The cutoff value of irregularity was calculated based on the ROC curve. Cox proportional hazards regression models were used to test associations between features and outcome. RESULTS: Of all the 217 patients included in the study, 67 patients had disease progression and 30 patients died. The cutoff value of the irregularity was selected to be 0.5335. Adrenal invasion, presence of distant metastasis and irregularity of tumors were significantly associated with PFS, and presence of distant metastasis and irregularity of tumors were significantly associated with OS. CONCLUSIONS: For patients with tumors larger than 7 cm in RCC, we found a radiological index that is closely related to the prognosis: irregularity. This is an unreported independent prognostic risk factor that can be quantified before surgery.

Predictive Factors for Acute Kidney Injury and Long-Term Renal Function Loss After Partial Nephrectomy: A Prospective Single-Center Study.

OBJECTIVE: To find factors related to postoperative acute kidney injury and long-term significant renal function (RF) loss after partial nephrectomy (PN) in Chinese population. METHODS: The main outcome was significant RF loss during the last follow-up, which was defined as >25% decrease in estimated glomerular filtration rate. RESULTS: A total of 416 patients were included with median age as 57 (interquartile ranges,IQR 49.8-65.0) year with body mass index as 24.2 (IQR 22.0-26.5) kg/m2 and preoperative estimated glomerular filtration rate as 90.5 (IQR 79.8-101) mL/min. Summarily, 259 (62.3%) patients were male, 54 (13%) had diabetes, 180 (43.3%) hypertension and 80 (19.2%) hyperuricemia. Median (IQR) tumor diameter was 3.1 (2.4-4.1) cm. All patients underwent PN, in which 135 (32.5%) by open PN approach, 109 (26.2%) by laparoscopic PN and 172 (41.3%) by robot assisted PN. RF was followed up for 16.88 (10.15-36.37) months, where 58 (13.9%) patients suffered significant RF loss. Multivariable analysis showed age (P = .0039), body mass index (P = .0049), diabetes (P = .0351), operative time > 110 minutes (P = .0034), diameter classification by Diameter-Axial-Polar score (diameter 2.4 cm-4.4 cm, P = .0225: diameter > 4.4 cm, P = .0207), postoperative acute kidney injury (P < .001) to be predictors of RF loss with area under the curve as 0.850. CONCLUSION: We prospectively found predictive factors of short and long-term significant RF loss in all operative methods and constructed a clinical nomogram for long-term Chinese patients RF loss.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis.

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Prognostic value of tumour contour irregularity on surgical strategies for T1bN0M0 renal cell carcinoma: A multi-institutional study.

PURPOSE: To determine the prognostic value of tumour contour irregularity degree (CID) in surgical strategy options for T1bN0M0 renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a retrospective multi-institutional review of 489 patients with T1bN0M0 RCC treated between January 2009 and June 2019. Cox regression and Kaplan-Meier analyses were performed to analyse the impact of CID on disease-free survival (DFS). RESULTS: The median follow-up time was 55 months (interquartile range, 40-81 months) for 55 (11.2 %) patients with metastasis or recurrence. Logistic analysis indicated that CID was associated with World Health Organization/International Society of Urological Pathology (WHO/ISUP) grades III-IV (odds ratio, 1.015; 95 % confidence interval [CI], 1.008-1.023; p < 0.001). After being classified into high CID (≥50 %) and low CID (<50 %) groups, those with a high CID showed a significantly higher ratio of WHO/IUSP grades III-IV (74/277 [26.7 %] vs 25/212 [11.8 %]) and shorter DFS than the low CID group (p < 0.001). Multivariable Cox regression showed that partial nephrectomy (PN; hazard ratio [HR], 1.889; 95 % CI, 1.020-3.499; p = 0.043), high CID (HR, 6.685; 95 % CI, 2.776-16.100; p < 0.001), and WHO/ISUP grade III-IV (HR, 1.950; 95 % CI, 1.100-3.458; p = 0.022) were independent prognostic factors for DFS. The Kaplan-Meier plot showed that PN had a DFS rate comparable to that of radical nephrectomy (RN; p = 0.994). In the low CID group, patients who underwent PN showed comparable DFS to those who underwent RN (p = 0.903). Furthermore, patients with a high CID tended to have worse DFS in the PN versus RN group (p = 0.044). Multivariable Cox regression showed that PN (HR, 2.049; 95 % CI, 1.065-3.942; p = 0.032) and WHO/ISUP grade III-IV (HR, 2.148; 95 % CI, 1.189-3.881; p = 0.011) were independent prognostic factors of DFS in the high CID group. CONCLUSIONS: CID is a reliable preoperative parameter which is positively correlated with WHO/ISUP grade and can help with surgical decision-making in patients with T1bN0M0 RCC.

Factors influencing the e-health literacy in cancer patients: a systematic review.

PURPOSE: As Internet technology evolves, electronic health (e-health) literacy gradually becomes a key factor in healthy behaviors and health-related decision-making. However, little is known about the influencing factors of e-health literacy among cancer survivors. Thus, the objective of this study was to systematically review the status quo, assessment tools, and influencing factors of e-health literacy in cancer patients. METHODS: We conducted a comprehensive search in several databases, including PubMed, MEDLINE, Embase, CINAHL, PsycInfo, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese BioMedical Literature Database, and Chinese Science and Technology Journal Database between January 2000 and December 2021. RESULTS: A total of nine articles were included in this review, all of which were cross-sectional studies. Following the JBI critical appraisal tool, seven of them were rated as high quality. The e-Health Literacy Scale (eHEALS) was the most commonly used measurement for e-health literacy in cancer patients. The level of e-health literacy in cancer survivors was not high, which was associated with a variable of factors. The behavioral model of health services use was adopted to summarize related influencing factors. From an individual's perspective, predisposing characteristics and enabling resources were the most significant factors, without factors related to needs characteristics. CONCLUSION: The study has identified the influencing factors of e-health literacy among cancer survivors, including age, gender, domicile place, education level, information-seeking behavior, and social support. In the future, e-health literacy lectures need to be carried out for elderly cancer patients, especially those who live in rural areas and have no access to the Internet. Families and friends of cancer survivors should also be encouraged to offer them more support. IMPLICATIONS FOR CANCER SURVIVORS: These findings of this review provide novel insights for both family members and medical workers to improve e-health literacy in cancer patients. Further research is required to develop easy-to-use electronic health information acquisition devices and establish propagable e-health literacy intervention programs for cancer survivors.

Does intraoperative cyst rupture of malignant cystic renal masses really have no negative impact on oncologic outcomes?

BACKGROUND: To assess the impact of malignant cystic renal masses (CRM) rupture on oncologic outcomes. METHODS: The study included 406 cases with partial nephrectomy (PN) and 17 cases with cyst decortication confirmed as malignant CRM by pathology. Recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used to identify risk factors associated with RFS, MFS, CSS, and OS. Logistic regression was performed to explore predictors of rupture. RESULTS: Tumor rupture occurred in 32 of 406 cases (7.9%). With median follow-up of 43 months, 4 (12.5%) and 5 (1.3%) cases experienced recurrence in rupture and non-rupture group, respectively (P = 0.003). Estimated RFS, MFS, and CSS were shorter in cyst ruptured (CR) group than non-ruptured (nonCR) cases (P < 0.001; P = 0.001; P < 0.001). Cox regression analysis indicated that CR was an independent prognostic factor for RFS (HR = 7.354; 95% CI = 1.839-29.413; P = 0.005), MFS (HR = 8.069; 95% CI = 1.804-36.095; P = 0.006), and CSS (HR = 9.643; 95% CI = 2.183-42.599; P = 0.003). Multivariable logistic regression showed that Bosniak IV was a protective factor for CR (OR = 0.065; 95% CI = 0.018-0.239; P < 0.001). However, compared to Bosniak III and I-IIF, Bosniak IV CRMs showed higher rate of clear cell renal cell carcinoma (ccRCC) (76.8% vs 36.5% vs 81.4%) (P < 0.001) and lower rate of Fuhrman I staging (11.2% vs 66.7% vs 7.4%) (P < 0.001). Therefore, in ruptured cases, the recurrence rate was higher in CRM with Bosniak IV (50%, 2/4) than Bosniak I-III (4.4%, 2/45) (P = 0.029). CONCLUSIONS: Intraoperative malignant CRM rupture had negative impacts on oncologic outcomes. Bosniak IV was more aggressive than Bosniak I-III and had a higher risk of recurrence after rupture. However, Bosniak IV had a lower risk of rupture, which could weaken even cover-up of the true effect of tumor rupture on oncologic outcomes.

An immune-related gene signature for the prognosis of human bladder cancer based on WGCNA.

The innovation of immunotherapy was a milestone in the treatment of bladder cancer (BLCA). However, the treatment benefits varied by individual thus promoting the investigation of the biomarker of the patients. Unfortunately, there were not many effective predictive models, which were desired by clinicians, for BLCA that can predict the prognosis and benefit of immunotherapy. We constructed a three genes prognosis prediction model termed RiskScore based on the result of weighted correlation network analysis (WGCNA) from The Cancer Genome Atlas (TCGA) cohort (n = 406). We then validated the prediction accuracy with three validation cohort(GSE13507 (n = 165), GSE48075(n = 73), GSE32894(n = 224)). We compared the differences in gene expression, immune relate function, and immune infiltration between two groups divided by RiskScore. We further discovered the potential drug target and suitable compounds for high-risk groups. Our results suggested that the low-risk group may be more potential for immunotherapy for they have higher B cell infiltration, higher expression of immune checkpoints(PDCD1, CTLA4), and much more active immune-related pathways(B cell and T cell receptor signaling pathway). The RiskScore showed a well predictive accuracy for the prognosis of BLCA. After Spearman analysis, we found the suitable drug target and compounds for the patients in the high-risk group. The model we constructed is able to predict the prognosis of BLCA patients with ease and accuracy. PLK1 and gefitinib may be utilized for further treatment of BLCA patients.

Targeting the Mitochondria with Pseudo-Stealthy Nanotaxanes to Impair Mitochondrial Biogenesis for Effective Cancer Treatment.

The clinical success of anticancer therapy is usually limited by drug resistance and the metastatic dissemination of cancer cells. Mitochondria are essential generators of cellular energy and play a crucial role in sustaining cell survival and metastatic escape. Selective drug strategies targeting mitochondria are able to rewire mitochondrial metabolism and may provide an alternative paradigm to treat many aggressive cancers with high efficiency and low toxicity. Here, we present a pseudo-stealthy mitochondria-targeted pro-nanotaxane and test it against recurrent and metastatic tumor xenografts. The nanoparticle encapsulates a mitochondria-targetable pro-taxane agent, which can be converted into the chemically unmodified cabazitaxel drug, with further surface cloaking with a low-density lipophilic triphenylphosphonium cation. The resultant nanotaxane could be effectively taken up by cells and consequently specifically localized to the mitochondria. The in situ activated cabazitaxel causes mitochondrial dysfunction and ultimately results in potent cell apoptosis. After intravenous administration to animals, pro-nanotaxane mimics the stealthy behavior of polyethylene glycol-cloaked nanoparticles to provide a long circulation time. The antitumor efficacy of this mitochondria-targeted system was validated in multiple preclinical drug-resistant tumor models. Notably, in a patient-derived metastatic melanoma model that was initially pretreated with cabazitaxel, nanotaxane administration not only produced durable tumor reduction but also substantially suppressed metastatic recurrence. Taken together, these results demonstrate that this combination of a pseudo-stealthy platform with a rationally designed pro-drug is an attractive approach to target mitochondria and enhance drug efficacy.

Constant light in early life induces fear-related behavior in chickens with suppressed melatonin secretion and disrupted hippocampal expression of clock- and BDNF-associated genes.

BACKGROUND: Light management plays an important role in the growth and behavior of broiler chickens. Constant light in early post hatch stage has been a common practice in broiler industry for improving growth performance, while whether and how constant light in early life affects the behavior of broiler chickens is rarely reported. RESULTS: In this study, newly hatched chicks were kept in either constant (24 L:0 D, LL) or (12 L:12 D, LD) photoperiod for 7 d and then maintained in 12 L:12 D thereafter until 21 days of age. Constant light increased the average daily feed intake but not the body weight, which led to higher feed conversion ratio. Chickens in LL group exhibited fear-related behaviors, which was associated with higher corticosterone, lower melatonin and 5-HT levels. Concurrently, constant light exposure increased the mRNA expression of clock-related genes and suppressed the expression of antioxidative genes in the hippocampus. Moreover, brain derived neurotrophic factor/extracellular signal-regulated kinase (BDNF/ERK) pathway was suppressed in the hippocampus of chickens exposed to constant light in the first week post hatching. CONCLUSIONS: These findings indicate that constant light exposure in early life suppress melatonin secretion and disrupts hippocampal expression of genes involved in circadian clock and BDNF/ERK pathway, thereby contributing to fear-related behaviors in the chicken.

Constant light exposure in early life induces m6A-mediated inhibition of IGF gene family in the chicken.

Insulin-like growth factor (IGF) family plays important roles in regulating the development of various organ systems through stimulating cell proliferation and differentiation. Photoperiod is an important factor affecting growth and development in the chicken, yet the effect of constant light exposure in early life on IGF1 and IGF2 expression in the chicken remains unclear. In this study, one-day-old chickens were kept in either constant light (24L:0D, LL) or natural photoperiod (12L:12D, LD) for the first week of life and then maintained in constant light from 8 to 21 d of age. Constant light exposure in early life reduced mRNA expression of IGF gene family, including mRNA expression of IGF1, IGF2, and IGF2 binding proteins, in the hippocampus, hypothalamus, and liver of chickens at both 7 and 21 d of age. Moreover, constant light exposure increased mRNA expression of genes involved in RNA methylation N6-methyladenosine (m6A) in a tissue-specific manner. Interestingly, higher m6A on 3'UTR of IGF2 mRNA coincides with lower IGF2 mRNA, indicating a possible role of m6A in the post-transcriptional regulation of IGF2 expression in the hippocampus, hypothalamus, and liver of chickens. These findings suggest a m6A-mediated gene regulation of IGF gene family in different organs of chicken and expand our knowledge on mechanism of gene regulation in response to early life experience.

Light pollution has become a potential risk factor for the health of animals and humans. Aberrant light exposure (such as light at night and super-intensity light) induces sleep disturbances and mood disorders, as well as major depressive disorder. In poultry, photoperiod is an important factor affecting the growth and behavior of broiler chickens. The hippocampus is critical for the regulation of spatial memory and depression-like behaviors in birds and mammals. Insulin-like growth factor (IGF) family plays important roles in regulating the development of various organ systems through stimulating cell proliferation and differentiation in a tissue-specific manner. At present, broiler chickens are commonly reared under constant light (24 h light) in the first week after hatching, yet the effect of constant light exposure in early life on the expression of IGF family in the chicken remains unclear. In this study, 1-d-old Yellow-footed broiler chickens were kept in either constant light (24L:0D, LL) or natural photoperiod (12L:12D, LD) for the first week of life and then maintained in natural photoperiod from 8 to 21 d of age. We analyzed the mRNA expression and the post-transcriptional regulation of IGF2 expression in the hippocampus, hypothalamus, and liver of chickens. Constant light exposure in early life reduced mRNA expression of IGF gene family, including mRNA expression of IGF1, IGF2, and IGF2 binding proteins (IGF2BPs), in the hippocampus, hypothalamus, and liver of chickens at both 7 and 21 d of age. Our findings demonstrate the expression of IGF gene family in different organs of chickens and expand our knowledge on the mechanism of gene regulation in response to early-life experience.

Predictive value of renal tumor contour irregularity score in pathological T3a upstaging of clinical T1 renal cell carcinoma: A multi-institutional study.

PURPOSE: To explore the predictive value of renal tumor contour irregular degree (CID) in pathological T3a upstaging of clinical T1 renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a retrospective multi-institutional review of 1,487 patients with clinical T1N0M0 RCC between January 2009 and June 2019. Kaplan-Meier survival curve and Cox regressions were used to analyze the prognostic factors of disease-free survival (DFS). Logistic regressions were performed to determine predictors of pathological T3a upstaging in clinical T1 RCC. RESULTS: Among 1,487 patients with cT1 RCC, 96 (6.5%) were pathological T3a upstaging. Multivariable logistic regression analysis showed that age (odds ratio [OR] = 1.022, 95% confidence interval [CI] = 1.001-1.042, P = 0.036), tumor maximum diameter(OR = 1.242, 95% CI = 1.042--1.480, P = 0.015) and CID (OR = 1.067, 95% CI = 1.051-1.083, P < 0.001) were independent predictors of pathological T3a upstaging. The area under the curve (AUC) of the prediction model that included the CID was 0.846, while the AUC of the prediction model that did not include CID was only 0.741, the difference was statistically significant (P < 0.001). Kaplan-Meier survival curve showed that patients with pathological T3a upstaging had significantly worse DFS than patients without pathological T3a upstaging (P < 0.001). Multivariable Cox analysis showed that pathological T3a upstaging (HR = 1.836, 95% CI = 1.013-3.329, P = 0.002) is an independent prognostic factor for DFS in patients with cT1N0M0 RCC. CONCLUSIONS: The predictive model of CID combined with tumor maximum diameter and age significantly improved the ability to predict pathological T3a upstaging in clinical T1 RCC, compared with the prediction model of tumor maximum diameter combined with age. The predictive model of CID combined with tumor maximum diameter and age may be applicable to patients considering partial vs. radical nephrectomy.

MZINBVA: variational approximation for multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys.

As our understanding of the microbiome has expanded, so has the recognition of its critical role in human health and disease, thereby emphasizing the importance of testing whether microbes are associated with environmental factors or clinical outcomes. However, many of the fundamental challenges that concern microbiome surveys arise from statistical and experimental design issues, such as the sparse and overdispersed nature of microbiome count data and the complex correlation structure among samples. For example, in the human microbiome project (HMP) dataset, the repeated observations across time points (level 1) are nested within body sites (level 2), which are further nested within subjects (level 3). Therefore, there is a great need for the development of specialized and sophisticated statistical tests. In this paper, we propose multilevel zero-inflated negative-binomial models for association analysis in microbiome surveys. We develop a variational approximation method for maximum likelihood estimation and inference. It uses optimization, rather than sampling, to approximate the log-likelihood and compute parameter estimates, provides a robust estimate of the covariance of parameter estimates and constructs a Wald-type test statistic for association testing. We evaluate and demonstrate the performance of our method using extensive simulation studies and an application to the HMP dataset. We have developed an R package MZINBVA to implement the proposed method, which is available from the GitHub repository https://github.com/liudoubletian/MZINBVA.